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Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The...

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Autores principales: Coutinho Carneiro, Vitor, de Abreu da Silva, Isabel Caetano, Amaral, Murilo Sena, Pereira, Adriana S. A., Silveira, Gilbert Oliveira, Pires, David da Silva, Verjovski-Almeida, Sergio, Dekker, Frank J., Rotili, Dante, Mai, Antonello, Lopes-Torres, Eduardo José, Robaa, Dina, Sippl, Wolfgang, Pierce, Raymond J., Borrello, M. Teresa, Ganesan, A., Lancelot, Julien, Thiengo, Silvana, Fernandez, Monica Ammon, Vicentino, Amanda Roberta Revoredo, Mourão, Marina Moraes, Coelho, Fernanda Sales, Fantappié, Marcelo Rosado
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329083/
https://www.ncbi.nlm.nih.gov/pubmed/32609727
http://dx.doi.org/10.1371/journal.pntd.0008332
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author Coutinho Carneiro, Vitor
de Abreu da Silva, Isabel Caetano
Amaral, Murilo Sena
Pereira, Adriana S. A.
Silveira, Gilbert Oliveira
Pires, David da Silva
Verjovski-Almeida, Sergio
Dekker, Frank J.
Rotili, Dante
Mai, Antonello
Lopes-Torres, Eduardo José
Robaa, Dina
Sippl, Wolfgang
Pierce, Raymond J.
Borrello, M. Teresa
Ganesan, A.
Lancelot, Julien
Thiengo, Silvana
Fernandez, Monica Ammon
Vicentino, Amanda Roberta Revoredo
Mourão, Marina Moraes
Coelho, Fernanda Sales
Fantappié, Marcelo Rosado
author_facet Coutinho Carneiro, Vitor
de Abreu da Silva, Isabel Caetano
Amaral, Murilo Sena
Pereira, Adriana S. A.
Silveira, Gilbert Oliveira
Pires, David da Silva
Verjovski-Almeida, Sergio
Dekker, Frank J.
Rotili, Dante
Mai, Antonello
Lopes-Torres, Eduardo José
Robaa, Dina
Sippl, Wolfgang
Pierce, Raymond J.
Borrello, M. Teresa
Ganesan, A.
Lancelot, Julien
Thiengo, Silvana
Fernandez, Monica Ammon
Vicentino, Amanda Roberta Revoredo
Mourão, Marina Moraes
Coelho, Fernanda Sales
Fantappié, Marcelo Rosado
author_sort Coutinho Carneiro, Vitor
collection PubMed
description Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.
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spelling pubmed-73290832020-07-14 Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni Coutinho Carneiro, Vitor de Abreu da Silva, Isabel Caetano Amaral, Murilo Sena Pereira, Adriana S. A. Silveira, Gilbert Oliveira Pires, David da Silva Verjovski-Almeida, Sergio Dekker, Frank J. Rotili, Dante Mai, Antonello Lopes-Torres, Eduardo José Robaa, Dina Sippl, Wolfgang Pierce, Raymond J. Borrello, M. Teresa Ganesan, A. Lancelot, Julien Thiengo, Silvana Fernandez, Monica Ammon Vicentino, Amanda Roberta Revoredo Mourão, Marina Moraes Coelho, Fernanda Sales Fantappié, Marcelo Rosado PLoS Negl Trop Dis Research Article Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors. Public Library of Science 2020-07-01 /pmc/articles/PMC7329083/ /pubmed/32609727 http://dx.doi.org/10.1371/journal.pntd.0008332 Text en © 2020 Coutinho Carneiro et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Coutinho Carneiro, Vitor
de Abreu da Silva, Isabel Caetano
Amaral, Murilo Sena
Pereira, Adriana S. A.
Silveira, Gilbert Oliveira
Pires, David da Silva
Verjovski-Almeida, Sergio
Dekker, Frank J.
Rotili, Dante
Mai, Antonello
Lopes-Torres, Eduardo José
Robaa, Dina
Sippl, Wolfgang
Pierce, Raymond J.
Borrello, M. Teresa
Ganesan, A.
Lancelot, Julien
Thiengo, Silvana
Fernandez, Monica Ammon
Vicentino, Amanda Roberta Revoredo
Mourão, Marina Moraes
Coelho, Fernanda Sales
Fantappié, Marcelo Rosado
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
title Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
title_full Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
title_fullStr Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
title_full_unstemmed Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
title_short Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
title_sort pharmacological inhibition of lysine-specific demethylase 1 (lsd1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in schistosoma mansoni
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329083/
https://www.ncbi.nlm.nih.gov/pubmed/32609727
http://dx.doi.org/10.1371/journal.pntd.0008332
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